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【结 构 式】 
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【药物名称】XV-454 【化学名称】3-[2-[3-(4-Amidinophenyl)-4,5-dihydroisoxazol-5(R)-yl]acetamido]-2(S)-(3-methylphenylsulfonamido)propionic acid 【CA登记号】171028-74-3 【 分 子 式 】C22H25N5O6S 【 分 子 量 】487.53845 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antiplatelet Therapy, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
Preparation of intermediate (IV) is illustrated in Scheme 25654801a: Methyl N3-Boc-(S)-2,3-diaminopropionate (I) was condensed with m-toluenesulfonyl chloride (II) to provide sulfonamide (III). The Boc group was then deprotected with HCl in dioxan to give amine (IV).
| 【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (II) | 23316 | 3-methylbenzenesulfonyl chloride | 1899-93-0 | C7H7ClO2S | 详情 | 详情 |
| (III) | 28132 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C16H24N2O6S | 详情 | 详情 | |
| (IV) | 28133 | methyl (2S)-3-amino-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C11H16N2O4S | 详情 | 详情 |
合成路线2
Oxime (VI) was prepared from 4-cyanobenzaldehyde (V) upon treatment with hydroxylamine-HCl and pyridine. The nitrile oxide generated from oxime (VI) and NaOCl underwent a dipolar cycloaddition to methyl butenoate (VII) to produce the racemic isoxazoline (VIII). After conversion of the nitrile group of (VIII) to imidate (IX), reaction with methanolic ammonia yielded amidine (X), which was protected with Boc2O to give (XI). Hydrolysis of the methyl ester of (XI) with LiOH provided carboxylic acid (XII), which was coupled to amine (IV) using TBTU to afford amide (XIII) as a diasteromeric mixture. After Boc group removal by acidic treatment yielding (XIV), its methyl ester group was hydrolyzed with LiOH to afford the corresponding acid. The diastereomeric mixture of carboxylic acids was finally separated by preparative chiral HPLC.
| 【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 28133 | methyl (2S)-3-amino-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C11H16N2O4S | 详情 | 详情 | |
| (V) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (VI) | 17553 | 4-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (VII) | 28134 | methyl 3-butenoate | C5H8O2 | 详情 | 详情 | |
| (VIII) | 28135 | methyl 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C13H12N2O3 | 详情 | 详情 | |
| (IX) | 28136 | methyl 2-(3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C14H16N2O4 | 详情 | 详情 | |
| (X) | 28137 | methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (XI) | 28138 | methyl 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetate | C18H23N3O5 | 详情 | 详情 | |
| (XII) | 28139 | 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C17H21N3O5 | 详情 | 详情 | |
| (XIII) | 28140 | methyl (2S)-3-[[2-(3-[4-[[(tert-butoxycarbonyl)amino](imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C28H35N5O8S | 详情 | 详情 | |
| (XIV) | 28141 | methyl (2S)-3-[[2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C23H27N5O6S | 详情 | 详情 |